PROJECT SUMMARY The HIV epidemic among people who inject drugs (PWID) has been on the decline, but amidst a burgeoning opioid epidemic, communities are now increasingly vulnerable to HIV transmission. Recent HIV outbreaks linked to drug injection has introduced HIV into PWID networks and thus, potentially reverse decades of HIV prevention successes. While opioid agonist therapy (OAT) and syringe services programs (SSPs) reduce HIV transmission, access to and utilization of such programs are unavailable or with limited availability; sexual and injection-related HIV risks persist in many PWID. The integration of pre-exposure prophylaxis (PrEP) into existing evidence-based programs (e.g., OAT, SSPs) has been presented as an opportunity to strengthen HIV prevention efforts in PWID. Uptake, however, remains stubbornly low in PWID despite them being ideal candidates and interested in starting PrEP. Data from our ongoing PrEP adherence trial in PWID show high rates of attrition (43.7%) between the initial PrEP eligibility screening visit and PrEP initiation (usually 1-3 weeks). Further, qualitative interviews indicate preferences for PrEP delivery that would decrease waiting times or repeated visits altogether PrEP prescription. These early findings, supported by others, guide the need for rapid PrEP initiation integrated within an existing harm reduction services that reduce or eliminates patient, clinician, and structural barriers. Results from recent pilot studies have shown early acceptability, feasibility, and safety of rapid (same-day) PrEP initiation in men who have sex with men (MSM) and transgender women (TGW), but none of them include PWID, a group with extraordinary need in the current opioid crisis. Rapid PrEP initiation may be particularly important for PWID as they are more likely to be lost before treatment initiation. To fully optimize HIV prevention, PrEP care should be combined with OAT. Combining OAT with ART evolved from physicians who would withhold antiretroviral therapy (ART) from PWID if they were using drugs; if patients were OAT, ART prescription increased. Given the findings that advanced practice nurses (APNs) are more likely to inquire in a patient-centered manner about their drug use and provide more supportive counseling, a new differentiated care model of combined, same-day PrEP/OAT for PWID is well-suited to start with APNs. We, therefore, propose to develop and pilot test this model within an implementation science framework. The specific aims are to: 1) Aim 1: examine feasibility and acceptability among PWID and clinical stakeholders for an adapted APN-delivered, rapid HIV prevention program for PWID (iRaPID) that integrates same-day PrEP and OAT; and 2) Aim 2: estimate the preliminary efficacy of PrEP and OAT uptake in a pilot randomized controlled trial of the iRaPID vs. treatment as usual strategy in PWID without HIV. Together, these aims will address a wide gap in HIV prevention by addressing multilevel barriers to dispensing same-day combination prevention. Elements learned from a successful same-day PrEP/OAT model for PWID can guide future scale-up models that incorporate both APNs and physicians in urban and non-urban settings where resources are limited.